Transdermal therapeutic system

ABSTRACT

A therapeutic system for supplying active substances to the skin consists of a backing layer remote from the skin, with at least one active substance depot. The depot may consist of a fluid active substance or a fluid composition comprising an active substance delivery control matrix. There is also included an adhesive fixing device for fixing the therapeutic system on the skin. The therapeutic system is characterized in that the active substance depots ( 14 ) consist of at least one adjuvant having a supporting and distributing function by being provided with a planar textile material completely surrounded by matrix ( 12 ).

ThisThis application is a Reissue of application Ser. No. 08/469,207,U.S. Pat. No. 5,820,876, which is a continuation-in-part of applicationSer. No. 08/341,844, filed Nov. 18, 1994, now abandoned, which is acontinuation of application Ser. No. 08/027,698, filed May 17, 1993, nowabandoned, which is a division of application Ser. No. 07/908,930, filedJul. 8, 1992, now abandoned, which is a continuation of application Ser.No. 07/597,102, filed Oct. 12, 1990, now abandoned, which is acontinuation of application Ser. No. 07/219,066, filed Jun. 27, 1988,now abandoned, which claims priority of PCT application numberDE87/00372, filed Aug. 20, 1987, which claims priority of German PatentApplication P 36 29 304.0, filed Aug. 28, 1986.

FIELD OF THE INVENTION

The invention relates to a therapeutic system for applying activesubstances to the skin, with a backing layer remote from the skin, atleast one active substance depot, an active substance distributiondevice which is linked with the active substance depot, an activesubstance delivery control device controlling the delivery of the activesubstance through the system and a pressure sensitive adhesive fixingdevice for the therapeutic system on the skin, its use and process forthe production thereof.

BACKGROUND OF THE INVENTION

Therapeutic systems for the transdermal administration of medicamentssupply one or more active substances at a predetermined rate and incontinuous manner over a fixed period to a given application point onthe skin.

These systems are therapeutic precision instruments ensuring acontinuous active substance release.

Such therapeutic systems can have both a topical and a systemic actionand the large number of active substances which can be applied in thisway and their different chemical, physical and pharmacologicalcharacteristics make ever new demands on the production of such systems.

Conventionally these transdermal systems have at least one activesubstance reservoir, where the active substance is present in solid,liquid or disperse molecular form and an adhesion layer through whichthe system is closely connected with the skin and through which activesubstance transfer takes place, a control membrane andprotective/covering layers which are substantially impermeable for theactive substance.

The known systems are difficult to manufacture and have a complicatedstructure.

One problem of conventional systems is that of being able to processreadily volatile active substances, because the evaporation of theactive substance is difficult to control during production.

Thermally sensitive active substances can only be used to a limitedextent in the system in the case of matrices or therapeutic systemswhich have to be thermally treated and which are produced with heattreatment stages.

Attempts have already been made to introduce pure active substance infine-crystalline form into a pressure sensitive adhesive polymer, sothat the finely divided, fine-crystalline active substance dissolveswith time as depot crystals in the adhesive matrix layer (DE-OS 35 00508=U.S. Pat. No. 4,719,226). This process is not suitable for volatileand thermally sensitive active substances, because it includes thermaltreatment stages.

Another attempt to increase the capacity of such therapeutic systemscomprises embedding in a pressure sensitive adhesive layer of such asystem active substance depots in the form of microcapsules, which aresurrounded by a control membrane (see U.S. Pat. Nos. 3,598,123 and3,731,683). The production of such control membrane-surroundedmicrocapsules is extremely complicated and expensive and cannot beperformed for many active substances. The mixing of the activesubstance-containing microcapsules under a reservoir materialconstitutes a further difficult process stage, during which themicrocapsules can easily be damaged or destroyed, which can lead to anunsatisfactory constancy of the active substance content in the finishedtherapeutic system. The process of U.S. Pat. No. 3,598,123 is difficultto perform for liquid active substances, particularly if the liquidsubstance is present in readily volatile form.

German patent 3 424 837 discloses a depot plaster, which can be used forliquid materials and has a covering film, a liquid active substance inan outwardly bulging region of the covering film and a control membranecovering the active substance and permeable for the latter. Between thecovering film and the control membrane is provided an active substancedistribution device, namely a non-woven fabric, which uniformlydistributes the active substance liquid on the control membrane andwhich is effective over a large surface area. In the case of the depotplaster of German patent 3 424 837 the covering film and the controlmembrane are welded together in their outer regions in order to preventan outward flow of the liquid active substance.

However, the known depot plaster is disadvantageous in that the liquidtherein flows freely and can easily run out if the adhesive or weldededges are damaged and also requires an expensive control membrane, whichmust be provided in addition to the active substance distribution devicein order to kinetically control the delivery of the active substance.

The problem of the present invention is consequently to provide a noveltherapeutic system with active substance depot for the administration ofthe active substance, which can be manufactured less expensively andmore reliably than the prior art systems, which is also suitable forprocessing volatile and/or thermally unstable components.

SUMMARY OF THE INVENTION

According to the invention this problem is solved by a therapeuticsystem, which is characterized in that the active substance distributiondevice and the active substance delivery control device are a reservoirmatrix having one or more discrete active substance depots arranged in aspatially defined manner with respect to one another and having a higheractive substance concentration than in the reservoir matrix. During theproduction of the therapeutic system, the reservoir matrix can be freefrom active substances and is only enriched therewith over a period oftime, i.e. during the storage of the system or, in the case of highlyvolatile substances, during the production of the system. Thus, it is anadvantage of the invention that now active substances, which arethermally unstable and/or volatile can be introduced during manufactureinto transdermal systems in the form of a depot and without any thermalstressing. There is no need for stages, such as the mixing of thereservoir matrix material with the active substance, and instead saidmaterial becomes saturated with the active substance at room temperatureduring the storage of the therapeutic system. Production is simplifieddue to the omission of the production stages for the activesubstance-saturated matrix.

Due to the fact that here a reservoir matrix with its own controlfunction is used, which is inter alia determined by the migration speedof the active substance through the matrix, there is no need to providea control membrane, which requires additional process stages andmembrane material during production. The depot can consist of pureactive substance, which can be solid or fluid, but may contain alsoinert adjuvants. The term “inert” is here understood to mean that activesubstance and adjuvant do not react with one another. An “inert”adjuvant can also be a substance having physiological effects, such ase.g. dimethylsulfoxide (DMSO) or the like, which e.g. increases thepermeability of the skin. Suitable adjuvants are also support materialswhich make the active substance depot insensitive with respect topressure and tension application, as well as carriers. Thus, the supportmaterial may be an inert adjuvant of planar fabric material forproviding and supporting a distributing function. For example, anon-woven fabric may serve as an inert adjuvant and as the supportingfabric and assist the uniform distribution of nicotine or any otheractive substance referred to hereafter. In other words, such fabricmaterial will facilitate the processing of the active substance.

It is possible to use active substances which can be applied intransdermal manner and typical examples of these are given below.

Nicotine.

Corticosteroids: hydrocortisone, prednisolone,beclomethasone-propionate, flumethasone, triamcinolone,triamcinolone-acetonide, fluocinolon, fluocinolinacetonide,fluocinolon-acetonide acetate, clobetasolpropionate, etc.

Analgesics, anti-inflammatory agents: acetaminophen, mefenamic acid,flufenamic acid, diclofenac, diclofenac-sodium-alclofenac,oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylicacid, 1-menthol, camphor, sulindac-tolmetin-sodium, naproxen, fenbufen,etc.

Hypnotically active sedatives: Phenobarbital, amobarbital,cyclobarbital, triazolam, nitrazepam, lorazepam, haloperidol, etc.

Tranquilizers: fluphenazine, thioridazine, lorazepam, flunitrazepam,chloropromazine, etc.

Antihypertensives: pindolol, indenolol, nifedipin, lofexidin,nipradinol, bucumolol, etc.

Antihypertensively acting diuretics: hydrothiazide, bendroflumethiazide,cyclopenthiazide, etc.

Antibiotics: penicillin, tetracycline, oxytetracycline, fradiomycinsuflate, erythromycin, chloramphenicol, etc.

Anesthetics: lidocaine, benzocaine, ethylaminobenzoate, etc.

Antimicrobiological agents: benzalkonium chloride, nitrofurazone,nystatin, acetosulfamine, clotrimazole, etc.

Antifungal agents: pentamycin, amphotericin B, pyrrolnitrin,clotrimazole, etc.

Vitamins: vitamin A, ergocalciferol, chlolecalciferol, octotiamine,riboflavin butyrate, etc.

Antiepileptics: nitrazepam, meprobamate, clonazepam, etc.

Coronary vasodilators: dipyridamole, erythritol tetranitrate,pentaerythritol tetranitrate, propatylnitrate, etc.

Antihistamines: diphenyl hydromine hydrochloride, chlorpheniramine,diphenylimidazole, etc.

Antitussives: dertromethorphan (hydrobromide), terbutaline (sulphate),ephedrine (hydrochloride), salbutanol (sulphate), isoproterenol(sulfate, hydrochloride), etc.

Sexual hormones: progesterone, etc.

Thymoleptics: doxepin, etc.

Further medicaments/pharmaceuticals: 5-fluorouracil, fentanyl,desmopressin, domperdon, scopolamine (hydrobromide), peptide, etc.

Obviously, this list is not exhaustive.

Advantageously the active substance reservoir matrix can be built up inlayer form, the layers being the same or different. The reservoir matrixcan be pressure sensitive adhesive and can e.g. be a rubber material,such as styrene/isoprene/styrene block copolymers, silicone rubber orsynthetic resins, such as poly(meth)acrylate, polyurethane,polyvinylether, polyester, etc.—a list of suitable matrix materialsappearing e.g. in DE-OS 35 00 508, corresponding to U.S. Pat. No.4,719,226 the whole content of which is incorporated by reference. Itcan be advantageous if the reservoir matrix is pressure sensitiveadhesive, because this can obviate the need for providing a separatepressure sensitive adhesive fixing device in the system. The use of sucha pressure sensitive adhesive matrix is inter alia dependent on thecompatibility of the matrix material with the active substance. Pressuresensitive adhesive matrix materials are known.

Preferred non-pressure sensitive adhesive matrix materials are polymerscomprising poly(meth)acrylate, polyvinylpyrrolidone, ethylcellulose,hydroxypropyl-cellulose, hydroxypropylmethylcellulosephthalate,polyvinylalcohol or copolymers thereof with vinyllaurate or maleic acid,vinylacetate or copolymers thereof with vinyllaurate or maleic acid,polyvinylether, butylrubber and polycaprolactam.

For example, the active substance depot or depots can be introducedbetween a backing side reservoir matrix layer and a skin side reservoirmatrix layer, the thickness ratio of the reservoir matrix layerspreferably being between approximately X:Y=1:1 and 1:20 and inparticularly preferred manner 1:1 and 1:5.

It can be appropriate in other cases if the reservoir matrix orreservoir matrix layers from which said matrix is formed, to be providedat least on one side with pressure sensitive adhesive coatings.

According to a further advantageous development of the inventive system,the active substance depot can be arranged between the reservoir matrixand the backing layer, which is e.g. suitable for solid activesubstances which may be applied in the form of a corpuscle.

In a preferred embodiment of the invention the fixing device can beformed by adhesive portions embedded in the reservoir matrix, such ase.g. an all-round adhesive edge or adhesion points.

In conventional manner, it is possible to provide a detachableprotective layer for the surfaces of the therapeutic system facing theskin.

The sum of the active substance in the depot and reservoir matrix isadvantageously up to 20 times the therapeutically necessary activesubstance quantity.

A particularly preferred process for producing such systems comprisesthe reservoir matrix being formed from two reservoir matrix layers,which can be the same or different, between which is introduced theactive substance depot. The reservoir matrix layers can be joinedtogether by the application of pressure and/or heat. The depot can alsobe introduced into the reservoir matrix under pressure application, e.g.by injecting, for example, through a hypodermic syringe, a predeterminedquantity or pressing in an active substance corpuscle into a soft matrixlayer.

A further preferred process is forming at least part of the therapeuticsystem by strewing on particles.

It is also possible to produce a multilayer active substance matrix. Thecovering and reservoir matrix layer can also be joined by heat orpressure. The reservoir matrix layer or layers can at least partly beproduced from liquid materials, e.g. from a dispersion, a melt orsolutions.

The inventive therapeutic system is in particular suitable for local orsystemic transdermal active substance application in human or veterinarymedicine or can also be used in cosmetics.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is described in greater detail hereinafter relative tonon-limitative embodiments of the inventive therapeutic system and theattached diagrammatic drawings, which show:

FIG. 1 is a section through a preferred embodiment of an inventivetherapeutic system.

FIG. 2 is a section through a further preferred embodiment of atherapeutic system in which the active substance depot is locatedbetween the backing layer and the reservoir matrix.

FIG. 3 is a section through a further preferred embodiment of theinventive system, wherein the active substance reservoir is embeddedbetween matrix layers.

FIG. 4 is a section through an inventive therapeutic system with severalactive substance depots arranged in one plane.

FIG. 5 is a section through an inventive therapeutic system with anactive substance depot in layer form.

FIG. 6 is a section through a web-like semi-finished product accordingto the invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a section through an inventive therapeutic system, which isfixed to the skin 18 by a fixing device 16, e.g. a porous pressuresensitive adhesive layer or the like. On fixing device 16 is locatedreservoir matrix 12 which, at the time of production, is preferably freefrom active substance (active substance saturation taking place duringstorage). In the reservoir matrix 12 is embedded a depot 14, which isrepresented here as a solid active substance which dissolves in thereservoir matrix material 12 and is supplied to the skin 18 by fixingdevice 16. The therapeutic system is sealed to the outside by a backinglayer 10 which is impermeable for the active substance and preferablyalso moisture and simultaneously has a support function for the system.

FIG. 2 shows another variant of the inventive system, in which an activesubstance depot 14 is located on a reservoir matrix layer 12 and iscovered by a backing layer 10. The fixing device is not shown in thisdrawing and can e.g. be a pressure sensitive adhesive border or edge orthe like, which applies the skin contact surface of the therapeuticsystem closely to skin 18. This embodiment of the invention isadvantageous in that its production is very simple. It is merelynecessary to apply clearly defined quantities of active substance, inthe form of a solid or a viscous liquid to the prefabricated matrixlayer 12 and to seal or terminate the same by a backing layer 10.

The process for producing the system according to FIG. 2 is lessexpensive than for that according to FIG. 1. However, it can only beused if it is not absolutely necessary that active substance 14 isenclosed on all sides by matrix 12, e.g. due to the volatility of activesubstance 14 or due to a necessarily large contact surface betweenactive substance 14 and reservoir matrix 12. It is e.g. advantageous forsubstances which very readily dissolve in active substance 14 reservoirand without difficulty diffuse in it, so that there is no need for alarge contact surface between active substance 14 and active substancereservoir matrix 12.

FIG. 3 shows another preferred embodiment, in which an inventivetherapeutic system is fixed to the skin 18 by means of adhesiveparticles or portions 16 embedded on the skin 18 side in the activesubstance reservoir matrix material. The active substance reservoirlayer 12 here comprises an upper layer X and a lower layer Y, betweenwhich is introduced the active substance, which is e.g. here in liquidform. The provision of two reservoir matrix layers X, Y is advantageousif a system is being produced in such a way that firstly the loweractive substance reservoir layer Y is provided, optionally with analready coated on covering film or the like and then in accordance witha predetermined pattern the active substance/material is applied, thenext active substance reservoir layer X is superimposed, and finally inconventional manner the backing layer 10 or optionally various adhesivelayers 16 are applied to complete the system. It may also be appropriateto firstly place the two active substance reservoir layers X, Y on topof one another, then inject a predetermined quantity of active substancebetween the two reservoir layers X, Y and in this way keep evaporationof the active substance 14 to a minimum.

FIG. 4 shows an embodiment of an inventive transdermal system withseveral active substance depots 14 arranged in one plane and placedbetween a pressure sensitive adhesive layer 16 and a reservoir matrix12, layer 16 simultaneously fixing the backing layer 10 to thetransdermal system. The transdermal system is sealed by a detachableprotective layer 19.

FIG. 5 shows another embodiment of an inventive transdermal system, inwhich a backing layer 10 is coated on one side with an adhesive layer 16and on it is located active substance 14, optionally with adjuvants,such as material for facilitating processing of active substance 14(e.g. tabletting aids) or carriers, like fabrics and the like. To theflat active substance depot 14 is applied a reservoir matrix 12 which isin turn covered by a detachable protective film.

FIG. 6 shows the precursor of an inventive transdermal system, such asis obtained during a preferred production process. A web-like protectivecoating material 19, such as e.g. waxed paper or the like is covered bya reservoir matrix layer Y, which is here constructed in pressuresensitive adhesive manner and on same are located in accordance with apredetermined pattern of active substance depot bodies 14. Matrix layerY is covered by a second matrix layer X, which can e.g. comprise amaterial differing from that of layer Y. The second matrix layer X issealed by a backing film 10. Along the arrows are located the parting orseparating lines, along which the intermediate product is cut or punchedduring the production of the inventive transdermal systems and thenprepared in the usual way.

Typical thicknesses for inventive transdermal systems are in the case ofa total thickness of approximately 123 to 5550 μm, preferably 285 to1550 μm; thickness of the backing layer 8 to 150 μm and preferably 15 to100 μm; thickness of the reservoir 100 to 5000 μm, preferably 200 to1330 μm; thickness of the protective layer 15 to 400 μm, preferably 70to 150 μm.

For special application it is also possible to market the “semifinishedproduct” as such, so as to enable users to carry out the separation ofthe systems, so that the semifinished product acts in the manner of a“storage pack”.

Preferred examples of the invention are described below.

EXAMPLE 1 PRODUCTION OF A NICOTINE PLASTER

Nicotine plasters, such as are used to stop people from smoking, are,according to the invention, produced as follows.

A pressure sensitive adhesive material comprising 2.0825 kg of a 40%solution of a self-crosslinking acrylate copolymer, e.g. of2-ethyl-hexyl acrylate, vinyl acetate, acrylic acid and titanium chelateester, or DUROTAC 280-2416 of the firm National Starch/Chemical B.V. ina mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of anacrylic resin of dimethylaminoethylmethacrylate and neutral methacrylate(EUDRAGIT E 100 of the firm RÖHM PHARMA), and 20 g of a mixed acidictriglyceride of fractionated C₈-C₁₀ coconut fatty acids (Miglyol 812 ofthe firm Dynamit Nobel) are applied to a protective layervapor-deposited with aluminum on one side and abhesively finished onboth sides and the solvent is evaporated at 50° to 80° C. Anapproximately 300 g/m² layer is obtained. From the thus producedpressure sensitive adhesive layer are punched round discs with adiameter of 65 mm. The projecting edges are worked and central to thesame is applied in each case one circular disc of a non-woven fabrice.g. fibrous mixture of viscose staple cotton fiber 50:50 with asubstance weight of 80 g/m² and with a diameter of 40 mm. An example ofsuch a product is PARATEX II/80, a product of LOHMANN GMBH & CO KG.PARATEX is a registered trademark of Lohmann GmbH & Co. KG. To this isapplied nicotine as the active substance in solution (140 g nicotine in100 g of an acrylic resin of dimethylaminoethylmethacrylate and neutralmethacrylates (EUDRAGIT E 100 of the Firm RÖHM PHARMA) in 102 mgdoses/disc. The thus produced patches are immediately laminated with anicotine impermeable backing layer(a 15 μm thick polyester film on oneside of which aluminum is vapor deposited) and sealed in four-edgesealing bags of a suitable packing material. The depot side of thebacking layer may be layered with a layer of approximately 300 g/m² ofthe pressure sensitive adhesive layer, referred to above. The four-edgesealing bags may consist of a compound of paper (surface weight 50g/m²), aluminum 9 μm and Barex (trademark of the firm Vistron Corp.,Cleveland, Ohio, USA, for thermoplastic acrylonitrile-copolymers withnegligible gas permeability and great resistance to solvents) with 26g/m². Thus, those nitrile rubber modified acrylonitrile-methylacrylatecopolymers serve as nicotine barrier layer, the aluminium as a nicotinedegradation agent barrier, and the paper as a protective layer.

In the case of this example the non-woven fabric serves as thesupporting fabric and to assist the uniform distribution of the nicotineas an inert adjuvant as defined hereinbefore.

The chemical composition of Barex has been known to the public, as isevident from the publication of M.TH. Schuler in “Kunststoffe-Plastics”9/1974, pages 13-20. Particular reference is made to the title, page 13,left-hand column, lines 1 to 3 which both refer generally to“Barex-Harze”, page 14/14-16, page 17, right-hand column, section“Untersuchungen an Barex zur Zulassung durch die FDA”, lines 5-7 andpage 18, column 2, paragraph 2 referring to the approval of the US FDAand stating that Barex (without specific reference to Barex 210) isobtained by graft polymerisation (Pfropf-Polymerisation) of 73-77 partsof acrylonitrile and 23-27 parts of methyl acrylate in the presence of8-10 parts butadiene-acrylonitrile copolymer of 70% of butadiene, theparts and percents always being by weight. Moreover, the fact that Barexis a thermoplastic copolymer which has negligible gas permeability andgood resistance to solvents is, for example, evident from page 13,left-hand column, paragraph 1. Line 1 specifically recitesthermoplastic, while the sentence starting in line 5 reads intranslation as follows:

“As already the term “barring plastic” means, this novel material hasvery good barring properties against various gases such as oxygen,carbon dioxide (carbonic acid), nitrogen and also many chemical agentssuch as acids, alkalis and solvents”.

The next sentence refers to the copolymerization of acrylonitrile withselected monomers. Lines 7 to 13 of paragraph 2 of left-hand column ofpage 13 read in translation:

“Its (i.e. of Barex 210) permeability for oxygen and carbon dioxide isabout ten times smaller than that of other conventional bulk plastics.This modern plastic is particularly suitable for applications in whichglass-like clarity, prevention of loss of flavor and gas-impermeabilityare required.”

As used herein, the term “sealing bag” refers to a package or othercontainer which is generally flexible and is sealed on at least oneside. The sealing bags of this invention can comprise, for example, twosheets or lamina which have been joined along all edges; a single sheetor lamina which has been folded and sealed along all edges or along allnon-folded edges; a pouch or pocket which is sealed along one or moreedges; and the like.

The term “nicotine barrier” as used herein, implies that the barriermaterial is inert to nicotine and does not permit nicotine to migratethrough the material over a nicotine barrier material is a metal filmsuch as aluminum, which may be provided on one side with a protectivelayer, e.g. of paper.

The term “nicotine degradation agent barrier” refers to a barrier layerwhich is substantially impermeable to nicotine degradation agents, suchas oxygen and water in liquid or vapor form, and light. The inventionmay also be defined as a nicotine containment sealing bag comprising:

a) a nitrile rubber modified acrylonitrile-methyl acrylate copolymernicotine barrier having a volume enclosed therein;

b) a nicotine degradation agent barrier serving to prevent entry ofnicotine degradation agents into said volume; and

c) nicotine base within said volume.

Due to the fact that, according to the invention, an active substancesolution can be rapidly applied to a matrix layer and is then covered byan active substance impermeable covering layer, it is possible for thefirst time to obtain in a satisfactory manner well dosed nicotineplasters.

NICOTINE RELEASE TEST (IN VITRO)

A nicotine plaster produced according to Example 1 after removing theprotective layer is immersed in 80 ml of isotonic common salt solutionat 37° C. and the released nicotine quantity is determined liquidchromatographically after predetermined intervals. The release mediumvolume was chosen in such a way that “sink” conditions are obtained overthe entire test period. The following results were obtained:

Nicotine released in vitro per plaster:

after 2 hours: 23.90 mg/plaster

after 4 hours: 32.34 mg/plaster

after 8 hours: 41.50 mg/plaster

after 24 hours: 56.54 mg/plaster

EXAMPLE 2 PRODUCTION OF A NICOTINE PLASTER

Another nicotine plaster according to the invention may be inventivelyproduced as follows:

A pressure sensitive adhesive material (adhesive 1) comprising 1.9758 kgof a 40% solution of a self-crosslinking acrylate copolymer (DUROTAC280- 2416 of the firm Delft National & Chemical B.V.) in a mixture ofethyl acetate, ethanol, heptane and methanol, 189.7 g of an acrylicresin of dimethylaminoethylmethacrylate and neutral methacrylate(EUDRAGIT E 100 of the firm RÖHM PHARMA), and 20 g of a mixed acidictriglyceride or fractionated C₈-C₁₀ coconut fatty acids (Miglyol 812 ofthe firm Dynamit Nobel) are applied to a protective layervapor-deposited with aluminum on one side and abhesively finished onboth sides and the solvent is evaporated at 50° to 80° C. Anapproximately 440 g/m² layer is obtained. From the thus producedpressure sensitive adhesive layer are punched round discs with adiameter of 51 mm. The projecting edges are worked and central to thesame is applied in each case one circular disc of a non-woven fabric(fibrous mixture of viscose staple fibre/cotton 70:30 with a substanceweight of 40 g/m²—PARATEX III/40 of LOHMANN GMBH & CO KG) and with adiameter of 42 mm. To this is applied nicotine as the active substancein solution (140 g nicotine in 100 g of an acrylic resin ofdimethylaminoethylmethacrylate and neutral methacrylates—EUDRAGIT E 100of the Firm RÖHM PHARMA) in 46 mg doses/disc. The thus produced patchesare immediately laminated with a nicotine-impermeable backing layer (a15 μm thick polyester film, on one side of which aluminum isvapor-deposited having an approximately 110 g/m² coating of adhesive 1),and sealed in four edge sealing bags of conventional suitable compositepacking material.

In this case the non-woven fabric serves as the supporting fabric and toassist the uniform distribution of the nicotine as an inert adjuvant asdefined hereinbefore.

Due to the fact that, according to the invention, an active substancesolution can be rapidly applied to a matrix layer and is then covered byan active substance impermeable covering layer, it is possible for thefirst time to obtain in a satisfactory manner well dosed nicotineplasters.

NICOTINE RELEASE TEST (IN VITRO)

A nicotine plaster produced according to Example 2 after removing theprotective layer is immersed in 80 ml of isotonic common salt solutionat 37° C. and the released nicotine quantity is determined liquidchromatographically after predetermined intervals. The release mediumvolume was chosen in such a way that “sink” conditions are obtained overthe entire test period. The following results were obtained:

after 2 hours: 5.1 mg/plaster

after 4 hours: 7.2 mg/plaster

after 8 hours: 10.1 mg/plaster

after 24 hours: 16.5 mg/plaster

It is to be understood that the invention is not limited to nicotineplasters and the production thereof with the claimed build-up but thatother substances as preferred substances are mentioned in thespecification may be administered by this new therapeutic system.

What is claimed is:
 1. A sealing bag containing a nicotine patchcomprising: a) a butadiene-acrylonitrile modified acrylonitrile methylacrylate copolymer layer, and b) a composite layer comprising paper and,aluminum, c) wherein the layers form a bag which is sealed on fouredges, and d) wherein a nicotine patch is contained within said bag. 2.A sealing bag according to claim 1, wherein the copolymer layercomprises a copolymer formed from about 73-77 parts by weight ofacrylonitrile copolymerized with 23-27 parts by weight of methylacrylate in the presence of 8-10 parts by weight of butadieneacrylonitrile copolymer containing about 70% by weight of polymer unitsderived from butadiene.
 3. The sealing bag of claim 1 further comprisinga protective layer forming the external surface of said sealing bag. 4.The sealing bag of claim 2 further comprising a protective layer formingthe external surface of said sealing bag.
 5. The sealing bag of claim 1wherein said composite is disposed on the external surface of saidcopolymer layer.
 6. The sealing bag of claim 2, wherein said compositeis disposed on the external surface of said copolymer layer.
 7. Asealing bag containing a nicotine patch comprising a four edged sealingbag made of a composite comprising paper, aluminum and abutadiene-acrylonitrile modified acrylonitrile methyl acrylatecopolymer, and wherein the nicotine patch is contained within said bag.8. A sealing bag consisting of: a) a thermoplasticbutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, and b) a composite layer consisting of paper and aluminum, c)wherein the layers from a bag which is sealed on four edges, and d)wherein a nicotine patch is contained within said bag.
 9. A sealing bagcontaining a nicotine patch comprising a four edged sealing bag made ofa composite consisting of paper, aluminum and a thermoplasticbutadiene-acrylonitrile modified acrylonitrile methyl acrylatecopolymer, and wherein the nicotine patch is contained within said bag.10. A sealing bag according to claim 8, wherein the copolymer layercomprises a copolymer formed from about 73-77 parts by weight ofacrylonitrile copolymerized with 23-27 parts by weight of methylacrylate in the presence of 8-10 parts by weight of butadieneacrylonitrile copolymer containing about 70% by weight of polymer unitsderived from butadiene.
 11. The sealing bag of claim 8, wherein saidcomposite is disposed on the external surface of said copolymer layer.12. The sealing bag of claim 10, wherein said composite is disposed onthe external surface of said copolymer layer.
 13. The sealing bag ofclaim 8 further comprising a protective layer forming the externalsurface of said sealing bag.
 14. The sealing bag of claim 10 furthercomprising a protective layer forming the external surface of saidsealing bag.
 15. A sealing bag according to claim 7, wherein thecopolymer layer comprises a copolymer formed from about 73-77 parts ofacrylonitrile copolymerized with 23-27 parts by weight of methylacrylate in the presence of 8-10 parts by weight of butadieneacrylonitrile copolymer containing about 70% by weight of polymer unitsderived from butadiene.
 16. The sealing bag of claim 7, wherein saidcomposite is disposed on the external surface of said copolymer.
 17. Thesealing bag of claim 15, wherein said composite is disposed on theexternal surface of said copolymer layer.
 18. The sealing bag of claim 7further comprising a protective layer forming the external surface ofsaid sealing bag.
 19. The sealing bag of claim 15 further comprising aprotective layer forming the external surface of said sealing bag.
 20. Asealing bag according to claim 9, wherein the copolymer layer comprisesa copolymer formed from about 73-77 parts by weight of acrylonitrilecopolymerized with 23-27 parts by weight of methyl acrylate in thepresence of 8-10 parts by weight of butadiene acrylonitrile copolymercontaining about 70% by weight of polymer units derived from butadiene.21. The sealing bag of claim 9, wherein said composite is disposed onthe external surface of said copolymer layer.
 22. The sealing bag ofclaim 20, wherein said composite is disposed on the external surface ofsaid copolymer layer.
 23. The sealing bag of claim 9 further comprisinga protective layer forming the external surface of said sealing bag. 24.The sealing bag of claim 20 further comprising a protective layerforming the external surface of said sealing bag.
 25. A sealing bagcontaining a nicotine patch comprising a combination of a) abutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, and b) a layer comprising aluminum, wherein the layers form a bagwhich is sealed on all edges and the nicotine patch is contained withinsaid bag.
 26. A sealing bag containing a nicotine patch comprising a bagsealed on all edges made of a composite comprising an aluminum layer anda butadiene-acrylonitrile modified acrylonitrile methyl acrylatecopolymer layer, wherein the nicotine patch is contained within saidbag.
 27. A sealing bag consisting of a combination of a) a thermoplasticbutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, and b) an aluminum layer, wherein said layers form a bag which issealed on all edges and a nicotine patch is contained within said bag.28. A sealing bag containing a nicotine patch comprising a bag sealed onall edges comprising a composite consisting essentially of an aluminumlayer and a thermoplastic butadiene-acrylonitrile modified acrylonitrilemethyl acrylate copolymer layer, wherein the nicotine patch is containedwithin said bag.
 29. A sealing bag as claimed in claim 25, which issealed on four edges.
 30. A sealing bag as claimed in claim 26, which isa four edged sealing bag.
 31. A sealing bag as claimed in claim 27,which is sealed of four edges.
 32. A sealing bag as claimed in claim 28,which is a four edged sealing bag.
 33. A sealing bag as claimed in claim25, which further comprises a paper layer.
 34. A sealing bag as claimedin claim 26, wherein the composite further comprises a paper layer. 35.A sealing bag as claimed in claim 27, wherein layer (b) furthercomprises a paper layer.
 36. A sealing bag containing a nicotine patchcomprising a bag sealed on all edges comprising a composite consistingessentially of a paper layer, an aluminum layer and a thermoplasticbutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, wherein the nicotine patch is contained within said bag.
 37. Abag for a patch with an active substance comprising a sealing bag madeof a composite comprising an aluminum layer and abutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer wherein the patch with the active substance is contained withinsaid bag.
 38. The bag according to claim 37, where the active substanceis nicotine.
 39. The bag according to claim 37, wherein the sealing bagis sealed on four edges.
 40. The bag according to claim 37, wherein thecomposite further comprises a paper layer.
 41. A bag for a patch with anactive substance comprising a sealing bag made of a composite comprisinga degradation agent barrier layer for said active substance and abutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer wherein said layers are in contact with each other and the activesubstance is contained in the patch within said bag.
 42. The bagaccording to claim 41, wherein the sealing bag is sealed on four edges.43. The bag according to claim 41, wherein the composite furthercomprises a protective layer.
 44. The bag according to claim 43, whereinthe protective layer is paper and the active substance is nicotine. 45.A sealing bag containing a nicotine patch comprising a bag sealed on alledges made of a composite comprising an aluminum layer and abutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, wherein said layers are in contact with each other and thenicotine patch is contained within said bag.
 46. A sealing bagconsisting of a combination of a) a thermoplasticbutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer, and b) an aluminum layer, wherein the layers are in contact witheach other and form a bag which is sealed on all edges and a nicotinepatch is contained within said bag.
 47. A sealing bag containing anicotine patch comprising a bag sealed on all edges comprising acomposite consisting essentially of an aluminum layer and athermoplastic butadiene-acrylonitrile modified acrylonitrile methylacrylate copolymer layer, wherein said layers are in contact with eachother and the nicotine patch is contained within said bag.
 48. A sealingbag as claimed in claim 45, which is a four edged sealing bag.
 49. Asealing bag as claimed in claim 46, which is sealed on four edges.
 50. Asealing bag as claimed in claim 47, which is a four edged sealing bag.51. A sealing bag as claimed in claim 45, wherein the composite furthercomprises a paper layer.
 52. A sealing bag as claimed in claim 46,wherein layer (b) further comprises a paper layer.
 53. A sealing bagcontaining a nicotine patch comprising a bag sealed on all edgescomprising a composite consisting essentially of a paper layer, analuminum layer and a thermoplastic butadiene-acrylonitrile modifiedacrylonitrile methyl acrylate copolymer layer, wherein said layers arein contact with each other and the nicotine patch is contained withinsaid bag.
 54. A bag for a nicotine patch comprising a sealing bag madeof a composite comprising an aluminum layer and abutadiene-acrylonitrile modified acrylonitrile methyl acrylate copolymerlayer wherein said layers are in contact with each other and thenicotine patch is contained within said bag.
 55. The bag according toclaim 54, wherein the sealing bag is sealed on four edges.
 56. The bagaccording to claim 54, wherein the composite further comprises a paperlayer.
 57. A bag for a nicotine patch comprising a sealing bag made of acomposite comprising a degradation agent barrier layer for said nicotinepatch and a butadiene-acrylonitrile modified acrylonitrile methylacrylate copolymer layer wherein said layers are in contact with eachother and a nicotine patch is contained within said bag.
 58. The bagaccording to claim 57, wherein the sealing bag is sealed on four edges.59. The bag according to claim 57, wherein the composite furthercomprises a protective layer.
 60. The bag according to claim 57, whereinthe protective layer is paper.
 61. A sealing bag for an active substancethat can be applied in a transdermal manner comprising an acrylonitrilemethyl acrylate copolymer containing medicament barrier layer and analuminum-containing medicament-degradation agent barrier.
 62. Thesealing bag of claim 61, further including a paper protective layer. 63.The sealing bag of claim 61, wherein the transdermal substance isnicotine.
 64. The sealing bag of claim 62, wherein the transdermalsubstance is nicotine.
 65. The sealing bag of claim 61, wherein theactive substance that can be applied in a transdermal manner is sealedwithin same sealing bag.
 66. The sealing bag of claim 62, wherein theactive substance that can be applied in a transdermal manner is sealedwithin same sealing bag.
 67. The sealing bag of claim 65, wherein theactive substance is nicotine that can be applied in a transdermal mannerand is sealed within same sealing bag.
 68. The sealing bag of claim 66,wherein the active substance is nicotine that can be applied in atransdermal manner and is sealed within same sealing bag.